PROJECT SUMMARY/ABSTRACT Oncogene addiction, the phenomenon that inhibiting a single gene in a cancer cell can stop its proliferation, is a key motivation for pursuing targeted cancer therapy. However, a mechanism for how it is established and maintained is not known. There is a critical need to develop a systems-level understanding of how oncogene addiction is established and maintained. Not meeting this need would hinder efforts toward the rational discovery of targeted cancer therapeutics. The long-term goal of this research is to understand the molecular basis and systems-level logic of cancer development, maintenance, and therapeutic resistance, and to translate this understanding into targeted and durable cancer treatments. The overall objective of this project, which is the next step toward that goal, is to identify the molecular mechanism and systems-level logic of how addiction to a model oncogene, v-erbB, is established and maintained. The central hypothesis is that establishing v-erbB addiction is a form of cell-fate induction and is mediated by positive feedback. The rationale for the proposed research is that once a systems-level understanding of v-erbB addiction is developed, it will form a framework for understanding of oncogene addiction in other cancers, and therefore may lead to novel strategies for drug discovery. The central hypothesis will be tested through these specific aims: (1) Use mass spectrometry to identify the pathways involved in the establishment and maintenance of v- erbB addiction; (2) Build a mathematical model in order to identify network motifs that are important for establishing and maintaining v-erbB addiction; and (3) Use fluorescence microscopy to characterize the molecular mechanism underlying the establishment and maintenance of v-erbB addiction. The results of these studies will be a significant contribution because they are expected to deepen our understanding of how cancer develops, how the logic of a cancer cell differs from a healthy one, and how to rewire or destroy a cancer cell.